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1,3-Diphenyl-2-Propene-1-One-Based Natural Product Antidiabetic Molecules as Inhibitors of Protein Tyrosine Phosphatase-1B (PTP-1B)
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Vivek Asati
Present-day studies have indicated that PTP1B knockout animals demonstrated improved glucose tolerance, reduction in diet-induced obesity, and enhanced sensitivity of cells toward insulin.19 Similarly, the administration of PTP-1B antisense oligonucleotides showed improved insulin sensitivity and normalized the plasma glucose levels as a result of reduced enzyme expression.20 Clinical researches have indicated the role of PTP-1B inhibitors (ertiprotafib; discontinued from clinical trials due to lack of efficacy and trodusquemine; presently under clinical trials) in the dephosphorylation of IR and down regulation of insulin signaling pathway.21 The tyrosine mimetic comprising of negatively charged functionalized components like malonates, cinnamates, phosphonates, and carboxylates have been recognized as PTP-1B inhibitors with distinct advantages.22 These above collective evidence from genetic, pharmaceutical, physiological, and biochemical backgrounds have addressed toward the perspectives of PTP-1B inhibitors as the latest candidates in the management of hyper-glycemic episodes and related obesity. This exciting antidiabetic target (specifically type-II DM) will be of immense significance toward the development of potent low-molecular-weight inhibitors.23
Recent Perspectives Of Chalcone-Based Molecules As Protein Tyrosine Phosphatase 1b (Ptp1b) Inhibitors
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Vivek Asati
Generally, those compounds which increase the sensitivity of muscle and adipose to insulin (insulin sensitizers) are foremost choice for successful treatment of DM. For diabetotherapy, several enzyme inhibitors had been developed so far, of them Dipeptidyl Peptidase-4 (DPP-4) and PTP1B inhibitors are of foremost importance. These compounds prolong the duration of insulin by preventing its degradation/inactivation [8]. Protein Tyrosine Phosphatase 1B (PTP1B) inhibitors are the latest candidate for the management of diabetes. A large number of PTP1B inhibitors having tyrosine mimetic structures, functionalized with negatively charged moieties such as phosphonates, malonates, carboxylates, or cinnamates have been developed [9]. Recently, two inhibitors ertiprotafib and trodusquemine have advanced into clinical trials for the treatment of diabetes and obesity. Although, the second phase clinical trial for ertiprotafib was discontinued due to lack of efficacy [10]. Natural and semi (synthetic) chalcones have shown significant anti-diabetic property by inhibiting PTP1B enzyme without showing major associated diabetic complications. At present, these inhibitors have not received adequate attention and need further exploration regarding efficacy and toxicological profiles to develop as formulations.
The importance of including the C-terminal domain of PTP1B1-400 to identify potential antidiabetic inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Andrea Coronell-Tovar, Francisco Cortés-Benítez, Martin González-Andrade
Many of the inhibitors reported in past years have used the short form of PTP1B to perform inhibition or kinetic assays. For example, N-aryl oxamic acid35, Ertiprotafib20, Celastrol36, use the hPTP1B1-285. 3-bromo-4,5-bis(2,3-dibromo-4,5-dihydroxybenzyl)-1,2-benzenediol (BDB)21, 2-(oxaloamino) benzoic acid (OBA)37, 2-(hydroxy-phenoxy) acetic acid38, Chlorogenic acid (CGA), Cichoric acid (CHA)39, Sodium orthovanadate (SO)39–42, use the hPTP1B1-321. In recent years the inhibitors Trodusquemine7,43, Ertiprotafib18, and Celastrol36 have reported inhibition parameters using both the short and complete forms of PTP1B (hPTP1B1-321 and hPTP1B1-400). For the Trodusquemine, the reported Ki are 4.0 and 0.6 µM for the short and long forms, respectively, about 6-fold lower with hPTP1B1-405. The same happens with celastrol, where IC50 are reported using PTP1B1-298 (IC50=4.8 µM) and PTP1B1-393 (IC50=2.1 µM), double the value using the short form.
Discovery of drugs that directly target the intrinsically disordered region of the androgen receptor
Published in Expert Opinion on Drug Discovery, 2020
The single stereoisomer of EPI-001, EPI-002, was assigned the generic name Ralaniten by the USAN council and a new stem class ‘-aniten’ created based upon its novel mechanism of action that distinguishes it from the C-terminal LBD nonsteroidal antiandrogens with the stem name ‘lutamide.’ Since the original discovery of EPI-067, approximately 500 analogs of this compound have been tested by the Sadar Lab for potential clinical development as a therapeutic and also as an imaging agent. In 2015, the prodrug of ralaniten, ralaniten-acetate also known as EPI-506, entered first-in-human clinical trials, thereby being the first drug that directly binds to an IDR to ever be tested in clinical trials. Trodusquemine/MSI-1436 has also been tested in clinical trials but it first binds to a folded region and then to an IDR of PTP1B [69]. Trodusquemine originated from a natural compound isolated from the dogfish shark, Squalus acanthias [70].
Identification of flavonolignans from Silybum marianum seeds as allosteric protein tyrosine phosphatase 1B inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Ningbo Qin, Tatsunori Sasaki, Wei Li, Jian Wang, Xiangyu Zhang, Dahong Li, Zhanlin Li, Maosheng Cheng, Huiming Hua, Kazuo Koike
Protein tyrosine phosphatase 1B (PTP1B) is a non-transmembrane protein tyrosine phosphatase1, expressing ubiquitously in the classical insulin-targeted tissues, and negatively regulating insulin and leptin signalling pathway2. Inhibition of PTP1B has been demonstrated beneficial effects, such as increased insulin sensitivity, improved glucose tolerance, and resistance to high-fat-induced weight gain, but without side effects3. Thus, PTP1B inhibitors have attracted much attention for anti-diabetes and anti-obesity drug developments4. Recently, PTP1B also found a positive role in the tumorigenesis of breast cancer and colorectal cancer, extending the application of PTP1B inhibitors as anti-cancer agents5. Up to date, several PTP1B inhibitors, such as ertiprotafib6, and trodusquemine7, have been developed into clinical trials. Despite the fact that chemical synthetic PTP1B inhibitors have reached to quite potent inhibitory activities, some barriers are remaining, such as low PTP selectivity, low bioavailability, and insufficient in vivo efficacy8. In contrast, natural products are recognised as another important resource to discover novel PTP1B inhibitors9.